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TRANSCRIPT
Department of Psychiatry
Helen J. Burgess, Ph.D.
Professor, Department of Psychiatry
Sleep and Circadian Research Laboratory
University of Michigan, Ann Arbor
Light Treatment:
Where Have We Come From
and Where Can We Go?
Conflict of Interest Disclosure
1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or
services consumed by, or used on, patients, OR
2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services
consumed by, or used on, patients.
Type of Potential Conflict Details of Potential Conflict
Grant/Research Support
Consultant Natrol, LLC – exogenous melatonin manufacturer
Speakers’ Bureaus
Financial support
Other
3. The material presented in this lecture has no relationship with any of these potential conflicts, OR
4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references
are provided as support for this lecture:
1.
2.
3.
Outline
• Human circadian system
• measuring the clock
• phase shifting the clock
• Circadian misalignment
• night work
• social jet lag
• Light Treatment
• chronic pain:
• fibromyalgia
• low back pain
• post-traumatic stress
Lig
ht
Outline
• Human circadian system
• measuring the clock
• phase shifting the clock
• Circadian misalignment
• night work
• social jet lag
• Light Treatment
• chronic pain:
• fibromyalgia
• low back pain
• post-traumatic stress
Lig
ht
The Central Circadian System
Period
~24.2 h
Emens & Burgess, Sleep Med Clin 2015
The Central Circadian Clock
Burgess & Eastman, J Biol Rhythms, 2008
>70% humans
have an endogenous
circadian period >24 h
→ Most of us have a
natural tendency to drift
later (phase delay)
→ Most of us need to shift
earlier (phase advance)
to stay in sync with the
external 24 h day
circadian period
The Central Circadian System
Emens & Burgess, Sleep Med Clin 2015
The Dim Light Melatonin Onset (DLMO)
• gold standard circadian phase marker in humans• melatonin must be measured in dim light (~6h before sleep onset)
• time when melatonin levels rise above a threshold• often occurs about 2-3 h before habitual lights off• key to diagnosis of circadian rhythm disorders vs. insomnia• key to optimal treatment of circadian rhythm disorders
17 18 19 20 21 22 23 240
2
4
6
8
10
12
1
Clock Time (h)
Saliv
ary
Me
lato
nin
(p
g/m
l)
Outline
• Human circadian system
• measuring the clock
• phase shifting the clock
• Circadian misalignment
• night work
• social jet lag
• Light Treatment
• chronic pain:
• fibromyalgia
• low back pain
• post-traumatic stress
Lig
ht
Chronic circadian misalignment produces adverse cardiometabolic
consequences: obesity, diabetes, cardiovascular disease
Circadian Misalignment
Scheer et al. PNAS 2009
Short term changes:
Sleep efficiency ↓20%
Leptin ↓17%
Glucose ↑6%
Insulin ↑ 22%
MAP ↑ 3%
Leproult et al. Diabetes 2014
Evidence to support an intrinsic adverse effect of circadian
misalignment on glucose metabolism, independent of sleep
Social Jet Lag
Light /Dark Clock
Wittmann et al. Chronobiol Int 2006
Social Jet Lag & Health
Social Jetlag = ▲sleep midpoint work days vs. days off
Social jet lag ≥ 2 hours:
↑ depression
↑ alcohol, nicotine, caffeine
↑ BMI if already overweight
↑ resting heart rate (5 bpm in healthy people)
↑ HbA1c
↑ C-reactive protein
↓ HDL
↑ triglycerides
Wittman et al. Chronobiol Int 2006
Levandovski et al. Chronobiol Int 2011
Roenneberg et al. Curr Biol 2012
Rutters et al. J Biol Rhythms 2014
Parsons et al. Int J Obesity 2015
Wong et al. JCEM 2015
Outline
• Human circadian system
• measuring the clock
• phase shifting the clock
• Circadian misalignment
• night work
• social jet lag
• Light Treatment
• chronic pain:
• fibromyalgia
• low back pain
• post-traumatic stress
Lig
ht
The Central Circadian System
Emens & Burgess, Sleep Med Clin 2015
Minors, D. S. and J. M. Waterhouse
(1981). Circadian Rhythms and the
Human. Bristol, John Wright & Sons.
Rütger Wever
passed away August 13, 2010 (87 years).
Lewy, A. J., T. A. Wehr, F. K. Goodwin, D. A.
Newsome and S. P. Markey (1980). "Light
suppresses melatonin secretion in humans."
Science 210(4475): 1267-1269.
Al Lewy, M.D., Ph.D.
Modern humans spend ~90%
of their time indoors
Primary Circadian Photoreceptor (ipRGCs)
400 500 600 7000.00
0.25
0.50
0.75
1.00
Wavelength (nm)
Rela
tive S
en
sit
ivit
y S-ConeM-ConeL-ConeRodMel
~480 nm
90% Americans report using technological device in hour before bedtime
(National Sleep Foundation, 2011)
n=55 healthy subject
18-30 years
10-2,000 lux for 5 hours
Mean ED50 = 26 lux
Range 6-350 lux
2019
Light Phase Response Curve
Hours Before and After the DLMO
- 9 - 3 0 3 6 9 12 15- 6
Ph
ase S
hif
t (h
)
Dela
yA
dvan
ce
Symbol for DLMO
~ 3500 lux for 2 h
S L E E P0
1
2
3
-1
-2
-3
Reduced sensitivity
Delay (move later)
NIGHT
Advance (move earlier)
MORNING
0
2
4
6
8
10
12
14
16
19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time of day (h)
Mela
ton
in (
pg
/ml)
0
2
4
6
8
10
12
19 21 23 1 3 5 7 9 11 13 15
Time of day (h)
Many subjects receive light at
different times relative to DLMO
Mela
tonin
(pg/m
l)
Primary Circadian Photoreceptor (ipRGCs)
Amygdala
LeGates et al.
Nature Rev Neurosci 2014
~480 nm
Sleep: van Maanen et al., SMR, 2015
• meta-analysis of 13 light treatment for
insomnia studies:
sleep quality, symptoms g=0.80
TST, WASO g=0.47
Mood: Al-Karawi and Jubair, J Affective Disorders, 2016
• 9 trials (n=419) in nonseasonal depression
• 2-5 week morning light treatment vs. placebo
Morning light reduced depression d=0.62
Effect size similar to antidepressants
cones +rods
Bright light may increase serotonin levels in the brain
Pain - Fibromyalgia
• antidepressants, antiepileptics: small Tx effects, side effects
• CBT – somewhat effective
• exercise – requires high patient motivation
• light treatment – minimal side effects, available, affordable
Burgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
John Burns, PhD
Morning Light
TreatmentSleep Pain
Circadian
Mood
Pain - Fibromyalgia
• n=10 women previously diagnosed with fibromyalgia (22-59 years)
• 2010 ACR criteria, including normal blood test results
• normal CBC, and normal ESR or CRP [medical record verified]
• symptoms present ≥ 3 months
• pain sufficiently widespread and severe
Burgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
Pain - Fibromyalgia
Burgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
1
2 Nap
3
4
5
6
7
8
9
10
11
12
13
14
15 END
PM AM
D
A
Y
O
F
S
T
U
D
Y
START
L
I
G
H
T
AMN 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
[
N 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
Sleep at Home on usual schedule
[ Sleep in Clinic- PSG ]
Sleep in Clinic - PSG ]
Home Visit
Sleep at Home on usual schedule
[
n=4
n=6
Assessed baseline
and post treatment:
DLMO
FIQ
Heat pain threshold
Heat pain tolerance
1
2 Nap
3
4
5
6
7
8
9
10
11
12
13
14
15 END
PM AM
D
A
Y
O
F
S
T
U
D
Y
START
L
I
G
H
T
AMN 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
[
N 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
Sleep at Home on usual schedule
[ Sleep in Clinic- PSG ]
]
Home Visit
Sleep at Home on usual schedule
[ Sleep in Clinic - PSG
Light ended at
average bedtime
Light started at
average wake time
Placebo to light box?
Home light box treatment
Burgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
Subject burden:
• sitting in front of light box for 1 hour a day
• rearrangement of living room space, extension cords, impact on family
White
broad
spectrum
light
No UV
Light
readings to
confirm
>3,000 lux
Tape
String
• Function and pain sensitivity improved after morning and evening light
• larger effects after morning light
• clinically meaningful improvement in function after morning lightBurgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
Pain - Fibromyalgia
Equal treatment
expectations
85% compliance
≈ CBT
~½ exercise training
24% improvement from baseline
12% improvement from baselineClinically meaningful improvement
≥14% improvement from baseline
Bennett J Rheumatol 2009
• Circadian phase advancing (shifting earlier) associated with
improvements in function and pain sensitivityBurgess, Park, Ong, Shakoor, Williams & Burns, Pain Medicine, 2017
Pain - Fibromyalgia
r=0.47, p=0.21
r=0.63, p=0.067 r=0.67, p=0.05
Suggests morning light
treatment should be
further investigated as a
potential adjunctive
treatment for chronic pain
FibroLight Study
• R21 NINR
• final sample of 60 people with fibromyalgia
• 4 week morning bright vs. dim [placebo] light treatment
To enhance effects on
sleep and mood
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
PM AM
D
A
Y
O
F
S
T
U
D
Y
PM AM
Sleep at Home on usual schedule
N 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
N 21 3 4 5 6 7 8 9 10 11 M 21 3 4 5 6 7 8 9 10 11 N
L
I
G
H
T
Lab Visit #1
Lab Visit #2 Home Visit #1
Lab Visit #4 Home Visit #3
Lab Visit #3 Home Visit #2
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
+ 30 day follow up
• Protocol: single arm (no placebo) open label trial
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
• Protocol: single arm (no placebo) open label trial (n=37)
• 10 females, 27 males; age 25-68 years
• Inclusion/exclusion criteria:
• self-report of chronic low back pain of ≥ 4/10, ≥ 6 months
• confirmed with previous report of back pain in medical record
• no other significant chronic disease
• medication controlled diabetes and hypertension ok
• no other significant chronic pain condition
• no psychosis, bipolar depression, suicidal ideation
• no high risk for sleep apnea, restless leg disorder, SAD
• no eye disease, no photosensitizing medications
• no previous experience with light treatment
• no daily medications that suppress melatonin (NSAIDs, beta-blockers)
• 5 veterans failed drug and alcohol testing, 7 more dropped out baseline
→ 25 veterans started light treatment, 1 dropped after 6 days for vacation
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
Baseline 6 Days 13 Days40
41
42
43
44
45
p=0.005
reduced p
ain
sensiti
vity
Pain
Th
resh
old
(d
eg
. C
)
Baseline 6 Days 13 Days46
47
48
reduced p
ain
sensiti
vity
Pain
To
lera
nce (
deg
. C
)
First feels painful Needs to stop
Semi-parametric generalized estimating equation regression model
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
Baseline 6 Days 13 Days40
45
50
55
wors
e p
ain
p=0.012
PR
OM
IS P
ain
In
ten
sit
y
Baseline 6 Days 13 Days54
55
56
57
58
59 p=0.006
more
pain
behavio
r
PR
OM
IS P
ain
Be
hav
ior
Baseline 6 Days 13 Days 54
55
56
57
58
59
wors
e p
ain
inte
rfere
nce
PR
OM
IS P
ain
In
terf
ere
nce
Baseline 6 Days 13 Days42
44
46
48
better
functio
n
p=0.08
p=0.01
PR
OM
IS P
hysic
al F
un
cti
on
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
Baseline 6 Days 13 Days4
5
6
7
8
9
more
depre
ssio
n
CE
S-D
Baseline 6 Days 13 Days30
35
40
45
more
anxie
ty
ST
AI
Baseline 6 Days 13 Days5
10
15
20
25
wors
e P
TS
D s
ym
pto
ms
p=0.0495
PC
L-
5
Pain – chronic low back pain in Veterans
Burgess & Burns, multi PI R34
Baseline 6 Days 13 Days4
6
8
10
wors
e s
leep
p=0.032
Pit
tsb
urg
h S
lee
p Q
uality
In
de
x
Baseline 6 Days 13 Days5
6
7
8
9
10
wors
e s
leep
p=0.028
p<0.001
Inso
mn
ia S
everi
ty In
dex
Reduction in pain possibly driven by
improvements in sleep quality and
circadian phase advance
∆ Pain interference and ∆ISI r=0.46, p=0.03
∆ Pain interference and ∆DLMO r=0.55, p=0.02
Suggests morning light treatment should be
further investigated as a potential adjunctive
treatment for chronic pain
Baseline 6 Days 13 Days18
19
20
21
late
r circadia
n tim
ing
p<0.0001
p<0.0001
Dim
Lig
ht
Me
lato
nin
On
se
t
Figure 2. Spectral power distribution of the bright vs. credible dim (placebo) Re-Timer®.
0.0E+00
1.0E-02
2.0E-02
3.0E-02
4.0E-02
5.0E-02
6.0E-02
7.0E-02
400 450 500 550 600 650 700
Re
lati
ve
sp
ec
tra
l p
ow
er
Wavelength (nm)
Bright (active)
Re-timer
Dim (placebo)
Re-timer
Spectrum
on inside of Re-timer®
Figure 3. Sample
data from the Re-
timer® light
treatment.
Top: Green light
indicates the bright
Re-timer® is on.
Bottom: Activity
indicates Re-timer®
is worn.
Wearable light treatment - Re-timer
placebo
compliance
Post-traumatic Stress Disorder
• Pilot study:
• n=15 probable PTSD (Criterion A trauma + PCL-5 >33)
• bright (n=9) vs. dim [placebo] (n=6) Re-timer for 4 weeks
Alyson Zalta, PhD
Baseline 6 Days 13 Days5
10
15
20
25
wors
e P
TS
D s
ym
pto
ms
p=0.0495
PC
L-
5
d=0.95 d=0.85
clinical trial NCT00701064
Zalta…& Burgess
Depression and Anxiety
2019
Post-traumatic Stress Disorder
K. Luan Phan, MD
Israel Liberzon, MD6 weeks in CBT in anxious patients
Emotional
faces task in
fMRI
n=30 healthy males
3 weeks of 30 mins of morning light, 100-10,000 lux
Amygdala reactivity in response to fearful faces, pre- to post- treatment
Morning bright light has potential to impact amygdala function
Post-traumatic Stress Disorder
• R61/R33 grant proposal – transdiagnostic:
• criterion A trauma in past 5 years + DASS >22
• 3 groups of 4 weeks of morning light with Re-timer:
•15 mins or 30 mins or 1 hour (~n=15 per group)
•Target engagement:
• dose response relationship b/n light “dose” and reduction in
amygdala reactivity d≥0.5
K. Luan Phan, MD
Israel Liberzon, MD6 weeks in CBT in anxious patients
Emotional
faces task in
fMRI
AcknowledgementsFaculty
Todd Arnedt, Ph.D.
Deirdre Conroy, Ph.D.
Leslie Swanson, Ph.D.
Clinical Coordinator
Ann Mooney, M.S.W.
Research AssistantsEmily Spence, B.A.
Katelyn Wilensky, B.S.
Nema Kebbeh, B.A.
Trevor de Sibour, B.S.
Lab Manager
Muneer Rizvydeen, B.A.
Registered Sleep TechnicianKelley Dubuc, RPSGT
Biostatistician
Myra Kim, PhD